Diazepam synthesis II2-amino-5-chlo

Diazepam synthesis II2-amino-5-chlorobenzophenone[3]Under Construction!2-amino-5-chlorobenzophenone alpha/beta-oxime[4]A mixture of 200g of 2-amino-5-chlorobenzophenone (compound 1, above), hydroxylamine hydrochloride and 100g of 1 liter of alcohol was stirred The mixture under reflux for 22h. to a small concentrated under vacuum was volume, with water diluted with sodium carbonate and neutralized was then added, and Benzene. the stirring was continued until a considerable amount of then crystalline precipitate was formed. Some petroleum ether had added, and the mixture was filtered The crude alpha-oxime. (139g, mp 150-160° C) remaining in the funnel was washed with petroleum ether and benzene. After recrystallization from a mixture of ether and petroleum ether, it forms colorless prisms melting at 164-167° C.The aqueous layer was discarded of the filtrate separated and dried, The organic solution. was concentrated in vacuum, and the residue taken up in The ether was ether. diluted solution with petroleum ether, filtered and kept at 0° C for The precipitated crystals 20h., a mixture of the isomers (42g, mp 119-122° C), was A third crop of filtered off. crystals from mother liquors was obtained after the concentration to a 8g of It consisted of sirup. prisms melting at 128-130° C This product can be recrystallized. from petroleum ether to form pure ether/beta-oxime, mp 129-132° C The total yield of 189g. (both alpha-and beta-oximes) corresponds to 89%.2-Amino-5-chlorobenzophenone beta-oxime (from the alpha oxime)[5]A solution of 20 grams of 2-Amino-5-chlorobenzophenone alpha-oxime (compound 2 above) of formic acid in 150 cc (98-100%) was refluxed for 3h, a small volume concentrated under vacuum to neutralized with NaOH and cooling with The precipitated quinazolide 3N 3-oxide. was filtered off and dissolved in alcohol, and after the 100ml of addition of 40 ml NaOH solution was refluxed for the 3N 15min. The solution was then partly concentrated in vacuum, and the precipitated by the addition of beta-oxime dry ice (solid CO2) It was extracted with ether and Prof. crystallized It formed by partial concentration. prisms (7.7 g) at 129-132° C melting.2-Chloroacetamido-5-chlorobenzophenone beta-oxime[5]Into a stirred, cooled (10-15° C) solution of 26.2 g (0.1 mole) of 2-Amino-5-chlorobenzophenone beta-oxime (compound 3 above) were introduced in 150 cc of dioxane in small portions of 12.4 g (0.11 mole), chloroacetyl chloride and sodium hydroxide an equivalent of chloroacetyl chloride 3N and sodium hydroxide The. solution introduced at such a rate were alternately as to keep the temperature below 15° C and neutral or slightly alkaline mixture. the The reaction was completed after 30 min with The mixture was then acidified. HCl, diluted with water and extracted with ether The ether extract was dried. concentrated under vacuum and the addition of ether to. Upon the oily residue, colorless prisms melting crystallized in the product at 166-167° C The yield was about 50%.7-Chloro-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one 4-oxide[5]To a solution of 6.4g (20 mmol) of 2-Chloroacetamido-5-chlorobenzophenone beta-oxime (compound 4 above) in 60cc of dioxane was added 20 cc of 1N NaOH. After 15h, the mixture was diluted with ice cold 1N NaOH and extracted with ether. The ether extracts was discarded, the alkaline solution acidified and extracted with methylene chloride. The organic solution was concentrated to a small volume, and diluted with petroleum ether, yielding 3.1g (54%) of the title compound.7-Chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one 4-oxide[5]To a stirred warm solution of 15 grams of 7-Chloro-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one 4-oxide (compound 5 above) in 700 cc of methanol were added 2.78 grams of sodium methoxide, and after 5 min, 5 cc of dimethyl sulfate. The reaction mixture was refluxed for 1 h, concentrated in vacuum to a small volume, and dilute with ether and petroleum ether. The formed crystals (11g, 70%) were filtered and washed with water. After recrystallization from acetone, colorless prisms melting at 188-189ฐC were obtained.Diazepam[5]A mixture of 3g of 7-Chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one 4-oxide (compound 6 above), 30 cc of chloroform and 1 cc of phosphorous trichloride was refluxed for 4 hours. The reaction mixture was then poured on ice and stirred with an excess of 40% NaOH solution. The chloroform solution was separated, dried with sodium sulfate, filtered and concentrated under vacuum. The residue was dissolved in methylene chloride and was crystallized by the addition of petroleum ether yielding 1.8g (63%) of the crystalline reaction product (mp 120-122ฐC). after recrystallization from a mixture of petroleum ether and acetone, the product formed colorless plates melting at 125-126ฐC.The same compound was also formed in almost quantitative yield by catalytic hydrogenation of compound 6 in methanol at atmospheric pressure (30-50ฐC) using Raney-Nickel as catalyst.